Methyl 3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside and processes for its preparation

ABSTRACT

Disclosed is methyl 3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside and processes for its preparation from methyl 3-azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside via the 4-bromo-4-deoxy intermediate; wherein the two inversions of configuration at C-4 result in a net retention of the α-D-arabino stereochemistry.

This is a division of application Ser. No. 248,178, filed Mar. 30, 1981,U.S. Pat. No. 4,348,325.

BACKGROUND OF THE INVENTION

This invention relates to the compound methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside (VI) andits utility in the synthesis of the known antibiotic (+)-thienamycin(I). ##STR1##

This invention also relates to processes for preparing VI from methyl3-azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside (IV). The followingscheme is representative of such processes: ##STR2## As described below,the process proceeding from starting material II, via the intermediate3-azido-3-deoxy sugar IV and 4-bromo-4-deoxy sugar V, performs aregioselective p-toluenesulfonylation of the C-3 hydroxyl of startingmaterial II to give tosylate III; a replacement of the C-3 tosylate withan azido function with retention of configuration at C-3 to afford IV;and two inversions of configuration at C-4 of IV with a net retention ofthe α-D-arabino stereochemistry in VI.

The utility of the resulting compound VI in the chiral total synthesisof thienamycin is described in copending, commonly assigned,concurrently filed U.S. patent application Ser. Nos. 248,177, now U.S.Pat. No. 4,384,998; 248,176, now U.S. Pat. No. 4,324,900; and 248,174;which are incorporated herein by reference to the extent that theydescribe the utility of compound VI. Also incorporated by reference isU.S. patent application Ser. No. 112,058 filed Jan. 14, 1980, nowabandoned, which describes the total synthesis of thienamycin and whichproceeds from an intermediate species which is common to the instantdisclosure and as described in the three previously mentioned,concurrently filed U.S. patent applications. Also incorporated byreference are U.S. Pat. No. 4,234,596 (issued Nov. 18, 1980), and EPOApplication No. 79,101,307-1 (publication No. 0007973 filed May 1,1979), which publications disclose schemes of total synthesis which canbe fed by common intermediates made available by the presently disclosedand claimed processes.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention may conveniently be represented bythe following reaction diagram: ##STR3## In words relative to the abovereaction sequence, the known starting methyl2,6-dideoxy-α-D-arabinohexopyranoside (II), in a solvent such aspyridine or dichloromethane, chloroform or the like is treated withp-toluenesulfonyl chloride, p-toluenesulfonic anhydride, or the like inthe presence of a base such as Et₃ N, iPr₂ NEt, pyridine,4-dimethylaminopyridine, or the like, at a temperature of from -15° C.to 10° C. from 24 hours to 10 days to yield the resulting C-3 tosylateIII, which upon treatment, in a solvent such as ethanol, methanol, orthe like, with alcoholic base, such as ethanolic sodium hydroxide,ethanolic potassium hydroxide, methanolic sodium hydroxide, methanolicpotassium hydroxide, or the like, followed by treatment with an alkaliazide, such as lithium azide, sodium azide, potassium azide, or the likein the presence of ammonium chloride at a temperature of from 50° C. to100° C. from 1 hour to 24 hours yields the azide IV.

Treatment of IV in a solvent such as dichloromethane, chloroform, or thelike with trifluoromethanesulfonyl chloride, trifluoromethanesulfonicanhydride, or the like in the presence of a base such as Et₃ N, iPr₂NEt, pyridine, 4-dimethylaminopyridine, or the like at a temperature offrom -76° C. to 0° C. from 20 minutes to 2 hours, (affording IVa),followed by treatment with a brominating agent, such as lithium bromide,sodium bromide, tetraethylammonium bromide, tetra-n-butylammoniumbromide, or the like in a solvent such as, dichloromethane,acetonitrile, tetrahydrofuran, dimethylformamide, or the like at atemperature of from 20° C. to 100° C. from 30 minutes to 5 hours, yieldsthe resulting 4-bromo-4-deoxysugar V, which upon treatment with sodiumcyanide, potassium cyanide (in the presence or absence of a crownether), tetraethylammonium cyanide, tetra-n-butylammonium cyanide,tetraethylammonium chloride-sodium cyanide, or the like in a solventsuch as dichloromethane, acetonitrile, tetrahydrofuran,dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or thelike at a temperature of from 30° C. to 150° C. from 15 minutes to 24hours yields the desired material VI.

Intermediate IV can also be transformed into VI via the4-chloro-4-deoxy- or 4-deoxy-4-iodo-tetradeoxy-D-lyxopyranosides, Va orand Vb, respectively, in a similar manner as that described for the4-bromo-4-deoxy derivative V. ##STR4## Chloride Va can be obtainedeither directly from IV by treatment with sulfuryl chloride in a solventsuch as dichloromethane, chloroform, diethyl ether, or the like, in thepresence of a base such as pyridine, triethylamine, i-Pr₂ NEt,4-dimethylaminopyridine, or the like, at a temperature of from -76° to30° for from 1 to 24 hours, or indirectly by nucleophilic displacementof the trifluoromethanesulfonyloxy group in IVa with chloride anion,such as tetra-n-butyl ammonium chloride. Iodide Vb is obtained bynucleophilic displacement of the trifluoromethanesulfonyloxy group inIVa with iodide anion, such as sodium iodide, potassium iodide,tetraethylammonium iodide, tetra-n-butylammonium iodide, or the like.Displacement of the chloro group in Va or the iodo group in Vb withcyanide anion, as described with bromide V, yields VI.

The desired compound VI may also be prepared by the following scheme:##STR5##

In words relative to the above reaction sequence, compound IV may betransformed into compound VI via intermediates IVa, IVb, IVc, and IVd.Preparation of IVa is already described in the process for compound V.Treatment of IVa with sodium acetate or benzoate, tetraethylammoniumacetate or benzoate, tetra-n-butylammonium acetate or benzoate, or thelike, in a solvent such as acetonitrile, dimethylformamide,dimethylsulfoxide, hexamethylphosphoramide, or the like at a temperatureof from 30° to 180° C. for from 15 minutes to 48 hours yields acetate orbenzoate IVb. De-esterification of IVb with methanolic sodium methoxideor the like affords methyl 3-azido-2,3,6-trideoxy-α-D-lyxohexopyranoside(IVc). Activation of IVc to afford IVd is carried out in like manner asthat described for activation of IV into IVa, and conversion of IVd intoVI by reaction with cyanide anion is performed in a similar fashion asthat described for conversion of V into VI.

In the foregoing word description of the above reaction diagram for thesynthesis of compound VI, it is to be understood that there isconsiderable latitude in selection of precise reaction parameters.Suggestion of this latitude and its breadth is generally indicated byenumeration of equivalent solvents system, temperature ranges,protecting groups and range of identities of involved reagents.

The following examples illustrate, but do not limit the product orprocess aspects of the present invention. All temperature expressionsare in °C.

EXAMPLE 1 Process for preparing Methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabinohexopyranoside STEP AMethyl 2,6-dideoxy-3-O-(p-toluenesulfonyl)-α-D-arabinohexopyranoside

To a solution of methyl 2,6-dideoxy-α-D-arabino-hexopyranoside (6.3 g,38.8 mmol) in pyridine (200 ml) at 0° C. is added freshly recrystallizedp-toluenesulfonyl chloride (7.6 g, 39.9 mmol). The mixture is kept 5days at 0° C., at which time additional p-toluenesulfonyl chloride (1.9g) is added. After 3 days at 5° C., the mixture is poured intoice-water, extracted several times with dichloromethane, the combinedorganic extracts evaporated under vacuum, coevaporated several timeswith toluene, and chromatographed on silica gel (Merck No. 7734) (1:2diethyl ether-petroleum ether, b.p. 35+-60° C.) to yield 8.5 g (69%) ofthe product as a solid; ¹ H NMR (300 MHz, CDCl₃): δ1.30 (d, C-CH₃), 1.83(td, H-2ax, J-H-1, H-2ax, 3.5 Hz, J H2eq, H2ax 12.8 Hz), 2.09 (m, H-2eq,J H-1, H-2eq 1.1 Hz, J H-2eq, H-3 5.5 Hz), 2.46 (s, ArCH₃), 2.53 (d,OH), 3.27 (s, OCH₃), 3.32 (td, H-4, J_(H-4-H-5) =J_(H-4), H-3 =8.8 Hz),3.65 (m, H-5), 4.68 (broad d, H-1), 4.74 (ddd, H-3), 7.38 (d, 2H, Ar),7.85 ppm (d, 2H, Ar); mass spectrum m/e 285 (M--OCH₃), 272 (M--CH₃ CHO).

Anal. C, H, S.

STEP B Methyl 3-Azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside

To a solution of methyl2,6-dideoxy-3-O-(p-toluenesulfonyl)-α-D-arabino-hexopyranoside (8.4 g,26.6 mmol) in absolute ethanol (80 ml) is added phenolphthalein (as anindicator) and subsequently dropwise at 60° C. saturated ethanolicsodium hydroxide until color persists for ˜10 minutes. The reactionmixture is then cooled to 10° C., the precipitated sodium tosylateremoved by filtration, the filtrate brought to pH 7 with 2 Nhydrochloric acid. Sodium azide (4.9 g) and ammonium chloride (2.9 g)are then added, and the mixture is stirred overnight at refluxtemperature. After concentration, the residue is partitioned betweendichloromethane and water, the aqueous layer extracted withdichloromethane, the combined organic extracts evaporated under vacuum,and chromatographed on silica gel (Merck No. 7734) (30:1 chloroformethylacetate) to afford the pure product as a colorless syrup; yield 3.7 g(74%); ¹ H NMR (300 MHz, CDCl₃): δ1.30 (d, C-CH₃), 1.73 (td, H-2ax,J_(H-1),H-2ax 3.6 Hz), 2.17 (m, H-2eq, J_(H-1), H-2eq 1.2 Hz, J_(H-2eq),H-3 5 Hz), 3.14 (t, H-4, J-_(H-3), H-4 =J_(H-4), H-5 =9 Hz), 3.34 (s,OCH₃), 3.63-3.79 (m, H-3,5), 4.75 (broad d, H-1); mass spectrum m/e 187(M), 156 (M--OCH₃), 145 (M-N₃), 143 (M--CH₃ CHO).

STEP C Methyl 3-azido-4-bromo-2,3,4,6-tetradeoxy-α-D-lyxohexopyranoside

To a solution of methyl3-azido-2,3,6-trideoxy-α-D-arabino-hexopyranoside (3.6 g, 19.2 mmol) indichloromethane (100 ml) cooled in an ice-bath are added pyridine (2 ml)and dropwise a solution of trifluoromethanesulfonic anhydride (3.2 ml,19.0 mmol) in dichloromethane (25 ml). After stirring for 10 minutes at0° C. with exclusion of moisture, additional pyridine (2 ml) andtrifluoromethanesulfonic anhydride (2.6 ml) are added. After 10 minutesat 0° C., the reaction mixture is diluted with dichloromethane (130 ml)and poured into a separatory funnel containing ice-water. The organiclayer is separated and washed with cold N hydrochloric acid, saturatedsodium hydrogencarbonate, water, and dried (sodium sulfate). Evaporationunder vacuum gives the 4-trifluoromethanesulfonate that is dissolved indry acetonitrile (50 ml) and treated with tetra-n-butylammonium bromide(12.7 g, 39.4 mmol) for 1 hour at 40° C. The reaction mixture isconcentrated, the residue partitioned between dichloromethane and water,the organic layer evaporated under vacuum and the resulting syrupchromatographed on a column of silica gel (Merck No. 7734) (1:2dichloromethane-hexane) to yield 3.65 g (76%) of the bromide; ¹ H NMR(300 MHz, CDCl₃): δ1.32 (d, C-CH₃), 1.90 (dd, H-2eq), 2.20 (td, H-2ax),3.36 (s, OCH₃), 3.84-400 (m, H-3,5), 4.27 (d, H-4), 4.86 ppm (d, H-1);mass spectrum m/e 250 (M).

STEP D Methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside

To a solution of methyl3-azido-4-bromo-2,3,4,6-tetradeoxy-α-D-lyxo-hexopyranoside (3.5 g, 14.0mmol) in freshly distilled acetonitrile (75 ml) is addedtetra-n-butylammonium cyanide (7.5 g, 28.0 mmol). The reaction mixtureis stirred for 1 hour at 50° C., cooled, partially concentrated (˜25ml), diluted with dichloromethane (250 ml), washed with water (3X),dried (sodium sulfate), and evaporated under vacuum. The residue ischromatographed on a column of silica gel (Merck No. 7734) (1:10 diethylether-hexane) to yield 687 mg (25%) of the desired cyanide as acolorless syrup; ¹ H NMR (300 MHz, CDCl₃): δ1.42 (d, C-CH₃), 1.60 (td,H-2ax, J_(H-1),H-2ax 3.5 Hz), 2.21 (m, H-2eq, J_(H-1), H-2eq 1.2 Hz,J_(H-2eq), H-3 5 Hz), 2.26 (t, H-4, J_(H-3), H-4 =J_(H-4),H-5 =10.8 Hz),3.36 (s, OCH₃), 3.92-4.06 (m, H-3,5), 4.85 (broad d, H-1); mass spectrumm/e 165 (M--OCH₃), 154 (M--N₃), 152 (M--CH₃ CHO).

What is claimed is:
 1. The compound having the structure: ##STR6## whichis methyl3-azido-4-C-cyano-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranoside.
 2. Thecompound: ##STR7##